Pharmaceutically effective novel 3,4-dihydro-1,2- and 1,3-thiozolo [4,3a] is

ABSTRACT

The invention relates to new thiazoloisoquinolines of the general formula (I), or salts thereof, ##SPC1## 
     Wherein 
     A stands for a group of the formula ##EQU1##  R 1  stands for hydrogen, hydroxy, alkoxy or aralkoxy, R 2  stands for hydrogen, hydroxy, alkoxy or aralkoxy, 
     R 3  stands for hydrogen, alkyl, aryl, nitro, carboxy or a carboxy derivative, and 
     Y stands for oxygen, sulfur, or a group of the formula =N--R 4 , wherein R 4  stands for hydrogen, alkyl, aryl, acyl, alkylsulfonyl or arylsulfonyl. 
     These new compounds can be used in practice as heart medicines or respiratory analeptics. 
     The new compounds according to the invention can be prepared as follows: an isoquinoline of the general formula (II) or a salt thereof ##SPC2## 
     Wherein 
     R 5  stands for hydrogen, hydroxy, alkoxy or aralkoxy, 
     R 6  stands for hydrogen, hydroxy, alkoxy or aralkoxy, 
     R 7  stands for hydrogen, alkyl, aryl, carboxy or a carboxy derivative, and 
     X stands for hydrogen, halogen or mercapto, 
     Is reacted with a reactive carbonic acid derivative, provided that at least one of the reactants contains a sulfur atom, and/or an isoquinoline of the general formula (III) ##SPC3## 
     wherein R 5 , R 6  and R 7  each have the same meanings as defined above, and Y&#39; stands for oxygen, sulfur or a group of the formula =N--R.sup. 8, wherein R 8  represents hydrogen, alkyl, aryl, acyl, arylsulfonyl or alkylsulfonyl, is oxidized, and/or substituents A&#39;, R 5 , R 6  and R 7  of the obtained thiazoloisoquinoline of the general formula (IA) ##SPC4## 
     wherein A&#39; stands for a group of the formula ##EQU2## and R 5 , R 6 , R 7  and Y&#39; each have the same meanings as defined above, are converted into those required in the end-products.

This invention relates to new sulfur-containing heterocyclic compoundsand pharmaceutical products containing the same, as well as to a processfor the preparation thereof.

The structures of the new sulfur-containing heterocyclic compounds,termed thereafter briefly as "thiazoloisoquinolines" are given byformulae (XII) and (XIII) along with the numbering of the ring system.##SPC5##

As shown by the above formulae, the new ring system encompasses twocondensed heterocycles. The 3,4-dihydro-1,3-thiazolo[4,3-a]isoquinolinesshown in formula (XII) contain a 1,3-thiazole ring condensed with anisoquinoline ring system. These compounds are termed hereafter brieflyas "1,3-thiazoloisoquinolines". In these compounds the carbon atom inposition 3, with two free valences, is in an oxidation state of 4, i.e.is a C³ carbonic acid derivative.

The 2H,4H-1,2-thiazolo[3,2-a]isoquinolines shown in formula (XIII)contain a 1,2-thiazole ring condensed with the isoquinoline ring system.These compounds are termed hereafter briefly as"1,2-thiazoloisoquinolines". In these compounds the carbon atom inposition 2, with two free valences, is in an oxidation state of 3, i.e.a C² carboxylic acid derivative.

The general symbols used in the specification and the claims to definethe individual substituents have the following meanings:

A stands for an ##EQU3## group, A' stands for an ##EQU4## group, R¹stands for hydrogen, hydroxy, alkoxy or aralkoxy,

R² stands for hydrogen, hydroxy, alkoxy or aralkoxy,

R³ stands for hydrogen, alkyl, aryl, nitro, carboxy or carboxyderivative,

R⁴ stands for hydrogen, alkyl, aryl, acyl, alkylsulfonyl orarylsulfonyl,

R⁵ stands for hydrogen, hydroxy, alkoxy or aralkoxy,

R⁶ stands for hydrogen, hydroxy, alkoxy or aralkoxy,

R⁷ stands for hydrogen, alkyl, aryl, carboxy or carboxy derivative,

R⁸ stands for hydrogen, alkyl, aryl, acyl, alkylsulfonyl orarylsulfonyl,

X stands for hydrogen, halogen or mercapto,

Y stands for oxygen, sulfur or =N--R⁴, and

Y' stands for oxygen, sulfur or =N--R⁸.

This invention relates to new thiazoloisoquinolines of the formula (I),##SPC6##

wherein the symbols have the meanings defined above. This inventionrelates further to pharmaceutical products containing as activeingredient these new compounds, as well as to a process for thepreparation of such active ingredients.

The compounds of the general formula can be prepared according to theinvention by reacting a compound of the formula (II) ##SPC7##

wherein the symbols have the meanings defined above, or a salt thereofwith a reactive carbonic acid derivative, provided that at least one ofthe reactants contains a sulfur atom, and/or by oxidizing anisoquinoline derivative of the formula (III) ##SPC8##

wherein the symbols have the meanings defined above, and/or byconverting substituents A', R⁵, R⁶ and R⁷ of the obtainedthiazoloisoquinolines of the formula (IA) ##SPC9##

into those required in the end-products. If desired, the obtainedthiazoloisoquinolines are converted into their salts, or the compoundsof the general formula (I) are liberated from the corresponding salts.

The compounds of the general formula (I) can be used primarily aspharmaceuticals or intermediates in the production of pharmaceuticallyactive substances. Certain members of this group exert a very favorableaction on the heart musculature, pulmonary circulation and on the oxygenconsumption of the heart musculature. The toxicity of these compounds islow. Accordingly, certain representatives of the compounds having theformula (I) can be used in practice as heart medicines. The othermembers of this group are respiratory analeptics.

As shown by formulae (II), (IV), (VI), (VII) and (VIII), ##SPC10##

all compounds of these groups may exist in at least two tautomericforms. The scope of the invention extends to all of these tautomers andtautomeric mixtures.

The carbonic acid-type reagent is chosen according to the substituent ofthe side chain attached to position 1 of the isoquinoline having theformula (II), and according to the substituent required in position 3 ofthe condensed ring system of the intermediate having the formula (IA).Thus, e.g. rhodanides, halocyanides, mono-thiocarbonic acid esters,thioureas, xanthates, cyanamides, acylisothiocyanates, carbon disulfide,etc. can be used as carbonic acid-type reagent. If desired, thesereagents can be formed directly in the reaction medium from theappropriate precursors.

According to one method of the invention an isoquinoline of the formula(IV), i.e. a compound containing a halogen-substituted side chain inposition 1, is used as the starting substance. This compound can bereacted with carbonic acid derivatives in various ways, to yield thecompounds of the general formula (IA) either directly or via one or moreother intermediates.

Condensed 1,3-thiazoloisoquinolines can be prepared directly from thecompounds of the general formula (IV) by reacting them withsulfur-containing carbonic acid derivatives capable of S-anionformation. These carbonic acid derivatives are reacted preferably in theform of their alkali metal, alkaline earth metal or ammonium salts. Ascarbonic acid derivatives, e.g. rhodanides, xanthates, salts ofmonothiocarbonic acid hemiesters, etc. can be used.

The reaction is carried out preferably in an alcohol or in anotherprotic solvent, such as in a formamide. As solvents, however, dipolaraprotic substances, e.g. dimethylformamide, dimethylsulfoxide, orhexamethylphosphoric acid triamide can also be used.

The reaction temperature is adjusted in accordance with the solventused. If a solvent with a boiling point lower than 100°C is used as thereaction medium, the reaction is carried out at the boiling point of thesystem whereas, when solvents of higher boiling points are used, thereaction temperature is between 80° and 120°C.

The products can be separated in crystalline form from the solvent,using optionally another solvent as precipitant.

As starting substances of the formula (IV) the ones containing a brominesubstituent in the side chain are utilized preferably. These compoundscan be prepared easily by the bromination of the appropriatelysubstituted 1-methylene-1,2,3,4-tetrahydroisoquinolines. According to apreferred method of the invention the obtained isoquinoline derivativecontaining a halogen-substituted side chain is reacted further directlyin the medium where it has been prepared, i.e. without isolation.

When reacting isoquinolines of the formula (IV) with othersulfur-containing carbonic acid derivatives, sulfur-containingisoquinoline intermediates of the formulae (III) or (VI) are obtained inone or more steps.

Thus, the salts of the mercapto-isoquinolines of the formula (VI) can beprepared by reacting an isoquinoline of the formula (IV) with thiourea,and decomposing the obtained isothiuronium salt with an alkali. Theobtained mercaptides represent a subgroup of the starting substanceshaving the formula (II), offering subsequent reactions described below.

When reacting the compounds of the formula (IV) with sodium thiosulfate,again isoquinolines of the general formula (VI) are obtained via theappropriate Bunte's salts.

The reaction of the isoquinolines of the general formula (VI),containing a mercapto group in the side chain, with a halocyanide,phosgene, thiophosgene, chloroformate or chlorothioformate yieldsdirectly the appropriately substituted 1,3-thiazoloisoquinolines.

The conditions of these reactions depend on the reactants utilized. Thereactants are generally given to the aqueous solution of the appropriatealkali metal salt of the thiolate. If the hydrolyzability of thereactant does not permit carrying out the reaction in an alkalinemedium, the reaction is carried out in a well stirred two-phase system.As water-immiscible solvents, preferably hydrocarbons or chlorinatedorganic solvents are used. In other cases dipolar aprotic solvents, e.g.dimethylformamide can be used to advantage. The reactions are in generalcarried out at low temperatures.

Similarly, the end-products can be obtained via intermediates byreacting the compounds of the general formula (IV), in the form of thecorresponding Grignard-reagents, with carbon disulfide. TheGrignard-reagent can be prepared in ether-type solvents, such as indiethyl ether, dioxane or tetrahydrofuran.

According to a further method of the invention isoquinolines of thegeneral formula (VII), constituting a subgroup of the compounds havingthe general formula (II), are used as starting substances. Thesecompounds can be reacted with sulfur-containing carbonic acidderivatives to yield the sulfur-containing isoquinolines, optionally viaone or more intermediates.

Thus, for instance, the compounds of the general formula (VII) can bereacted with acylisothiocyanates to yield the correspondingisoquinolines containing an N-acylimino substituent in the side chain.The acyl group of these substances can be split off, if desired. Theseacylated or deacylated intermediates can be used for the preparation of1,2-thiazoloisoquinolines containing an imino or =N-acyl substituent inposition 2 of the condensed ring system. In this latter case the acylsubstituent attached to the nitrogen atom may be benzoyl, alkylsulfonylor arylsulfonyl group.

The reaction with acylisothiocyanates is carried out preferably inacetone, chlorinated solvents, ketones, lower nitriles, ethers, etc.

According to a still further method of the invention the isoquinolinesof the general formula VIII (R³ = cyano or nitrile), containing acyanomethylene side chain and constituting a subgroup of the compoundshaving the general formula (VII), are reacted with hydrogen sulfide toyield the thiocarbamoyl-substituted intermediates of the general formula(IX). ##SPC11##

These latter compounds can be oxidized to yield the corresponding1,2-thiazoloisoquinolines. The reaction with hydrogen sulfide is carriedout preferably by introducing hydrogen sulfide gas into the system at 0°to 50°C, in the presence of a basic substance, e.g. triethylamine,piperidine or, preferably, pyridine. The addition of hydrogen sulfidecan be speeded up by the use of higher temperature in closed vessel.

By reacting the compounds of the general formula (VII) with ethylmagnesium bromide, a trans-Grignard reaction can also be carried out.During this reaction ethane is evolved, which is removed from the systemby heating. The reaction is carried out preferably in toluene, in thepresence of a small amount of ether. The reaction of the obtainedreagent with carbon disulfide also leads to the intermediates of theformula (III), containing a dithiocarboxy substituent in the side chain.

The compounds of the formula (VII) that contain a carbonylchloridesubstituent in the side chain can be converted into the isoquinolines ofthe general formula (X) in a reaction with sodium hydrosulfide.##SPC12##

The compounds of the formula (X), containing a thiocarboxy substituentin the side chain, constitute a subgroup of the compounds having theformula (III).

The isoquinolines of the formula (III) can be oxidized into the1,2-thiazoloisoquinoline end-products.

The oxidation can be carried out preferably with a halogen in thepresence of an acid binding agent. Thus, for example, the reaction canbe carried out with iodine or bromine in the presence of pyridine,quinoline, picoline, lutidine, etc. The reaction is in general conductedat a temperature of about 50°C.

It will be obvious to one skilled in the art that the carbonic acidderivatives used as reactants are selected generally in accordance withthe desired substituents of the 1,2- or 1,3-thiazoloisoquinolineend-products.

Thus, for example, a compound containing an imino group in position 3 ofthe condensed ring system can be obtained in a reaction with a rhodanideor halocyanide. O-Alkylmonothiocarbonate salts as reactants lead to theoxygen-substituted products, whereas alkyl xanthates to thecorresponding sulfur-substituted compounds.

Once the thiazoloisoquinoline ring system is built up, the substituentgroups introduced during ring closure can be converted into othergroups, and thus the compounds of the formula (IA) can be converted intothe compounds of the formula (I).

Thus, for example, the hydroxy groups attached to positions 8 and 9,respectively, can be alkylated or aralkylated, or the alkoxy or aralkoxygroups can be converted into hydroxy substituents. The ether bond can besplit by hydrogen halides, pyridine hydrochloride, etc. Alkoxy- andaralkoxy groups can be formed by reacting the hydroxy compounds withappropriate alkyl or aralkyl halides or sulfates in the presence of anacid binding agent. The ether bond of the benzyloxy derivatives can alsobe split by catalytic hydrogenation. In the alkoxy or aralkoxy groupsthe alkyl chain may contain preferably 1 to 4 carbon atoms, and the mostpreferred aralkyl group is benzyl.

The thiazoloisoquinolines containing a side-chain in position 1 to whicha group derived from a carbonic acid is attached can be converted intothe corresponding compounds containing a carboxy substituent in the sidechain.

The nitrile group in position 1 of the ring system can be converted intoan acid amide or carboxy group by treatment with an acid. In thisreaction preferably sulfuric acid is applied. The nitrile group inposition 1 can also be converted into carboxy group by treatment with abase. Alternately, the nitrile group can be converted into a carbalkoxygroup by acid-catalyzed alcoholysis. In turn, the acid amide group canbe dehydrated with phosphorous pentoxide, phosphorous oxychloride orthionyl chloride to yield the corresponding nitrile-substitutedcompounds. The nitrile group can also be converted into an acid amidegroup by treatment with a concentrated acid (e.g. sulfuric orpolyphosphoric acid) or with an alkaline hydrogen peroxide solution.

The compounds that contain a carboxy group in position 1 of thecondensed ring system can be esterified with alcohols inproton-catalyzed reactions. Alternately, these compounds can bedecarboxylated by heating.

The compounds wherein the side chain attached to position 1 of the ringsystem contains a methyl group can be converted into the correspondingcarboxy substituted compounds by oxidation with potassium permanganate.The imino groups attached to position 2 or 3, respectively, of thecondensed ring system can be alkylated with known alkylating agents,preferably after salt-formation with a strong base. For this purposee.g. sodium alcoholates, sodium amide or sodium hydride can be used.N-acylation can be carried out in pyridine medium with various acylatingagents, e.g. carboxylic chlorides, aryl or acylsulfonic acid chlorides,etc. The acyl group of the N-acylimino groups attached to position 2 or3, respectively, of the condensed ring system can be removed by acidhydrolysis.

The condensed-ring compounds containing an imino group can be reactedwith amine salts to yield the corresponding N-substituted derivatives.This reaction is carried out preferably in dimethylformamide, at theboiling point of the solvent.

The basic compounds of the general formula (I) can be converted intotheir salts by reacting them with mineral or organic acids, e.g.sulfuric, hydrochloric, phosphoric, nitric, acetic, rhodanic, propionic,lactic, malic, citric, succinic, maleic, fumaric, ethanedisulfonic,benzoic, salicylic, aspartic, etc. acids. Using polybasic acids, acidicsalts can be formed as well.

The compounds of the general formula (I) can be converted intopharmaceutical products, e.g. tablets, coated tablets, suppositories,capsules, solutions, powders, injectable preparations, etc. Thesecompositions may contain the active agents as such, or in admixture withcarriers, diluents and/or other additives.

In order to demonstrate the biological activity of the compoundsaccording to the invention, the pharmacological data of1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinoline(referred to hereinafter as compound "A") are listed below.

Compound A, administered in a dosage of 200 γ/kg. increases thecontractility of the heart musculature by 24% for 71 minutes, whereaswhen administering Carbochromen,(3-[β-2-diethylaminoethyl]-4-methyl-7-[carbethoxymethoxy]-2-oxo-1,2-chromen)in a dosage of 2 mg./kg., the same effect lasts only for 55 minutes.

Compound A, administered in a dosage of 100 γ/kg. into narcotized dogs,increases the cardiac output by 30%, and this effect lasts for 1.5hours. In contrast, Carbochromen, administered in a dosage of 2 mg./kg.,causes an increase of 25% and the effect lasts for 50 minutes.

Compound A, administered in a dosage of 200 γ/kg., decreases the totalperipheral resistance by 37% for 1.75 hours, whereas a 4 mg./kg. dosageof Carbochromen causes a decrease of 33% only for one hour.

Compound A, administered in a dosage of 100 γ/kg., decreases thepulmonary circulation resistance by 25% for one hour. A similar effectcannot be attained with the known agents.

Compound A, administered in a dosage of 200 γ/kg., increases thecoronary flow by 30% for 1.5 hours. In contrast, the known coronarydilatants produce this effect in much higher dosages and for muchshorter periods (10 to 60 minutes).

Compounds A, administered in a dosage of 200 γ/kg. into narcotized dogs,decreases the oxygen consumption of the left ventricle by 20%, and thiseffect lasts for 1 hour. In contrast, Carbochromen does not exert such aprolonged effect even in a tenfold dosage.

On this basis, compound A, administered in a dosage of 200 γ/kg.,increases the heart efficiency by 42%.

From the therapeutical indices, compound A appears to be 13.6 times moreactive than Carbochromen with respect to coronary flow, and 44 timesmore active with respect to the coronary resistance. Compound Aincreases significantly the flow and decreases the resistance for boththe femoral and the carotid vessels.

The fact that the above presented increase in total coronary flow afterCompound A is also reflected by a corresponding increase in thenutritional circulation of the myocardium as estimated by the H₂-washout method. The results show that the lasting effect of the drug onthe coronary flow is a useful action providing for a better oxygensupply of the myocardial fibres and is not due to some shuntingmechanism.

It can be also seen that after coronary occlusion the drug maytemporarily improve the blood supply to the ischemic area, whereas inthe non-infarcted area in the first 15 minutes after treatment, the druginduced increase is even somewhat higher than in the same area withoutocclusion.

Usefulness of Compound A as a potential antianginal drug is demonstratedby further experiments according to which it could significantly reducethe ischemic ST-segment elevation in the specific, effort typeantianginal test, consisting of a combination of coronary constrictionand cardiac overload induced by pacing. Similar effectiveness could beshown against pituitrin-induced T wave elevation in rats.

The drug exerts its effect also when administered by intraduodenalroute. 5 mg./kg. i.d. dosage evoked a marked increase in myocardialnutritional circulation, reaching values up to 30% and lasting for morethan 3 hours. However the drug was active already in oral doses as lowas 1 and 2 mg./kg. shown by the inhibition of the pituitrin inducedelevation of the T wave in rats.

The invention is elucidated in detail by the aid of the followingnon-limiting Examples.

EXAMPLE 1

0.7 g. of potassium rhodanide are dissolved in 20 ml. of hot dryalcohol, and 0.9 g. of1-chloromethyl-6,7-dimethoxy-3,4-dihydro-isoquinoline hydrochloride areadded to the boiling solution within 30 minutes. The reaction mixture isrefluxed for 3 hours, thereafter the solvent is evaporated, and theresidue is admixed with water. 0.9 g. of3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinerhodanide are obtained; m.p.: 220°C (after recrystallization from 96%alcohol).

Analysis: Calculated for C₁₄ H₁₅ N₃ S₂ O₂ (M = 321.42): C: 52.28 %, H:4.70 %, N: 13.07 %, S: 19.96 %; Found: C: 51.88 %, H: 4.68 %, N: 13.13%, S: 19.67 %.

1.0 g. of the above salt is dissolved in 20 ml. of hot water, and thesolution is rendered alkaline with 10% sodium hydroxide solution. Uponcooling, 0.8 g. of3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineseparates in crystalline state. M.p.: 145°C (after recrystallizationfrom a mixture of petroleum ether and benzene)

Analysis: Calculated for C₁₃ H₁₄ N₂ O₂ S (M = 262.32): C: 59.52 %, H:5.38 %, N: 10.68 %, S: 12.22 %. Found: C: 59.50 %, H: 5.12 %, N: 10.66%, S: 11.93 %.

0.5 g. of the above salt are dissolved in the mixture of 10 ml. of waterand 1 ml. of concentrated hydrochloric acid by heating, the solution isfiltered when hot, and allowed to cool. 0.5 g. of3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinehydrochloride separates in crystalline state; m.p.: 272°-274° C underdecomposition (after recrystallization from 96% alcohol).

Analysis: Calculated for C₁₃ H₁₅ N₂ O₂ SCl (M = 298.79): C: 52.29%, H:5.06%, N: 9.38%, S: 10.73%, Cl: 11.87%. Found: C: 52.11%, H: 5.16%, N:9.65%, S: 10.70 %, Cl: 11.60%.

EXAMPLE 2

According to a preferred method of the invention1-cyanomethylene-1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinoline isbrominated and reacted with rhodanide in a single step.

57.5 g. (0.25 moles) of1-cyanomethylene-1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinoline, 21.5 g.(0.255 moles) of sodium hydrocarbonate and 375 ml. of methanol areintroduced into a 2 l. flask equipped with a stirrer, reflux condenser,thermometer and addition funnel. The mixture is heated to boiling withstirring, thereafter it is cooled to 60°C, and 40 g. (0.25 moles) ofbromine are added dropwise to the solution within 20 minutes. During theaddition carbon dioxide evolves and leaves the system. Thereafter thesolution is boiled, and a solution of 40 g. (about 0.4 moles) ofpotassium rhodanide in 300 ml. of methanol is added. The separatedprecipitate temporarily dissolves, thereafter a loose, voluminousprecipitate separates. The mixture is boiled for 1.5 hours, thereafterleft to stand in a refrigerator overnight. The precipitate is filteredoff, suspended in 500 ml. of water, and 20 ml. of 1 n sodium hydroxidesolution are added to the suspension. The precipitate is filtered again,and washed with 3×100 ml. of water. 62.3 g. (86.8 %) of1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 229°-230°C (under decomposition).

EXAMPLE 3

4.0 g. of potassium rhodanide are dissolved in 200 ml. of hot dryalcohol, and 8.0 g. of1-(α-bromo)-cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineare added to the boiling solution within 30 minutes. The mixture isrefluxed for additional 4 hours, thereafter the solvent is evaporated invacuo, and the residue is triturated with water. This way 7.1 g. ofcrystalline1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 236°C (after recrystallization from butanol).

Analysis: Calculated for C₁₄ H₁₃ N₃ O₂ S (M = 287.33): C: 58.52 %, H:4.63 %, N: 14.63 %, S: 11.16 %. Found: C: 58.20 %, H: 4.45 %, N: 14.64%, S: 11.16 %.

EXAMPLE 4

2.0 g. ofS-(α-cyano-α-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuroniumbromide (prepared from1-(α-bromo)-cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolinewith thiourea; m.p.: 187°C under decomposition) are dissolved in 20 ml.of hot 50% alcohol. 5 ml. of 10% sodium hydroxide solution are added,and the mixture is refluxed for 15 minutes. Thereafter a solution of 0.5g. of cyanogen bromide in 5 ml. of alcohol is added, and the mixture isboiled for additional 0.5 hours. The solvent is evaporated in vacuo, andthe residue is triturated with water. 1.35 g. of1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 229°-230°C (under decomposition).

EXAMPLE 5

150 mg. of potassium rhodanide are dissolved in 5 ml. of hot dryalcohol, and 360 mg. of1-(α-bromo)-cyanomethylene-6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolineare added to the solution. The mixture is refluxed for 3 hours, thenevaporated to dryness. The residue is triturated with water. 220 mg. of1-cyano-3-imino-8,9-diethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 180°-182°C under decomposition (afterrecrystallization from butanol).

Analysis: Calculated for C₁₆ H₁₇ N₃ O₂ S (M = 315.39): C: 60.93 %, H:5.43 %, N: 13.32 %, S: 10.17 %, Found: C: 60.92 %, H: 5.49 %, N: 13.18%, S: 10.00 %.

Example 6

0.75 g. of O-ethyl-monothiocarbonate potassium salt (Benders' salt) aredissolved in 15 ml. of hot dry alcohol, and 1.55 g. of1-(α-bromo)-1-cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineare added to the boiling solution. The mixture is refluxed for 1 hour,thereafter the solvent is evaporated, and the residue is triturated withwater. 1.0 g. of1-cyano-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-onare obtained; m.p.: 205°-207°C (after recrystallization from butanol).

Analysis: Calculated for C₁₄ H₁₂ N₂ O₃ S (M = 288.32): C: 58.32 %, H:4.19 %, N: 9.72 %, S: 11.12 %. Found: C: 58.30 %, H: 4.17 %, N: 9.90 %,S: 11.26 %.

EXAMPLE 7

250 mg. of O-ethyl monothiocarbonate potassium salt are dissolved in 15ml. of hot dry alcohol, and 600 mg. of1-(α-bromo)-cyanomethylene-6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolineare added to the solution. The mixture is refluxed for 2 hours,thereafter the solvent is evaporated, and the residue is triturated withwater. 420 mg. of1-cyano-8,9-diethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-onare obtained; mp.: 172°-174°C (after recrystallization from butanol).

Analysis: Calculated for C₁₆ H₁₆ N₂ O₃ S (M = 316.37): C: 60.74 %, H:5.09 %, N: 8.86 %, S: 10.13 %. Found: C: 60.51 %, N: 4.93 %, N: 8.60 %,S: 9.79 %.

EXAMPLE 8

0.6 g. of potassium ethyl xanthate are dissolved in 8 ml. of hot dryalcohol, and 1.0 g. of1-(α-bromo)-cyanomethylene-6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolineare added to the boiling solution. The mixture is refluxed for 0.5hours, thereafter the solvent is evaporated, and the residue istriturated with water. 0.85 g. of1-cyano-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-thioneare obtained; m.p.: 228°C (after recrystallization from butanol).

Analysis: Calculated for C₁₄ H₁₂ N₂ O₂ S₂ (M = 304.38): C: 55.24 %, H:3.97 %, N: 9.20 %, S: 21.07 %. Found: C: 55.40 %, H: 4.08 %, N: 9.26 %,S: 21.30 %.

EXAMPLE 9

A methanol solution of 0.8 g. (0.01 moles) of bromine is added dropwise,at 30°-40°C, to the solution of 1.45 g. (0.005 moles) of1-(α-thiocarbamoyl)-cyanomethylene-1,2,3,4-tetrahydro-6,7-dimethoxy-isoquinolinein 25 ml. of dry pyridine. The mixture is stirred for one hour at thesame temperature, thereafter cooled to room temperature, and theseparated product is filtered by suction. 1.1 g. of1-cyano-2-imino-2H,4H-5,6-dihydro-8,9-dimethoxy-1,2-thiazolo[3,2-a]isoquinolinehydrobromide are obtained; m.p.: 276°-277°C under decomposition (afterrecrystallization from 50% ethanol).

Analysis: Calculated for C₁₄ H₁₄ N₃ O₂ BrS (M = 368.26): C: 45.65% H:3.83% N: 11.41% Br: 21.97% S: 8.71% Found: C: 45.88% H: 3.78% N: 11.66%Br: 22.05% S: 9.02%

EXAMPLE 10

2.0 g. of potassium rhodanide are dissolved in 30 ml. of hot dryalcohol, and a solution of 2.0 g. of1-(α-bromo)ethyl-6,7-dimethoxy-3,4-dihydro-1-isoquinoline hydrochloride(Arch, der Pharm. 277, 177 (1939) in 10 ml. of dry alcohol is addeddropwise to the boiling solution. The mixture is refluxed for 2 hours,thereafter the solvent is evaporated, and the residue is triturated withwater. 1.8 g. of1-methyl-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinerhodanide are obtained; m.p.: 218°-220°C (after recrystallization fromdry alcohol).

Analysis: Calculated for C₁₅ H₁₇ N₃ O₂ S₂ (M = 335.44): C: 53.71 %, H:5.11 %, N: 12.53 %, S: 19.12 %. Found: C: 54.02 %, H: 5.33 %, N: 12.65%, S: 19.29 %.

0.5 g. of the above salt are admixed with 10 ml. of ot water, and themixture is rendered alkaline with 10% sodium hydroxide solution. Uponcooling, 0.42 g. of1-methyl-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineseparates in crystalline state; m.p.: 145°-147°C (afterrecrystallization from alcohol).

Analysis: Calculated for C₁₄ H₁₆ N₂ O₂ S (M = 276.35): C: 60.84 %, H:5.83 %, N: 10.14 %, S: 11.60 %. Found: C: 61.12 %, H: 6.04 %, N: 10.02%, S: 11.82 %.

EXAMPLE 11

10 ml. of toluene and 2.0 ml. of phosphorous oxychloride are added to2.0 g. of N-(α-chloro-phenylacetyl)homoveratrylamine (prepared fromhomoveratrylamine with α-chloro-phenylacetylchloride; m.p.: 107°-109°C),and the mixture is refluxed for 2 hours. The mixture is evaporated todryness in vacuo, the residue is dissolved in 10 ml. of dry alcohol, andthis solution is again evaporated to dryness. The residue is dissolvedin 10 ml. of dry alcohol, and this solution is added dropwise to the hotsolution of 2.0 g. of potassium rhodanide in 40 ml. of dry alcohol. Themixture is refluxed for 2 hours, thereafter evaporated to dryness, andthe residue is triturated with water. 1.1 g. of1-phenyl-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinerhodanide are obtained; m.p.: 181°-183°C (after recrystallization fromdry alcohol).

Analysis: Calculated for C₂₀ H₁₉ N₃ O₂ S₂ (M = 397.51): C: 60.43 %, H:4.82 %, N: 10.57 %, S: 16.13 %. Found: C: 60.40 %, H: 5.15 %, N: 10.44%, S: 16.40 %.

1.0 g. of the above salt is admixed with 6 ml. of alcohol, the mixtureis rendered alkaline with 10% sodium hydroxide solution, thereafter themixture is diluted with 6 ml. of water. 0.8 g. of1-phenyl-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 123°-125°C (after recrystallization from 50%alcohol).

Analysis: Calculated for C₁₉ H₁₈ N₂ O₂ S (M = 338.42): C: 67.43 %, H:5.36 %, N: 8.28 %, S: 9.48 % Found: C: 67.13 %, H: 5.26 %, N: 8.34 %, S:9.34 %

1.0 g. of the above base is dissolved in 5 ml. of dry alcohol, and thesolution is acidified with dry alcoholic hydrochloric acid. 0.75 g. of1-phenyl-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinehydrochloride are obtained; m.p.: 264°-266°C under decomposition (afterrecrystallization from dry alcohol).

Analysis: Calculated for C₁₉ H₁₉ N₂ O₂ SCl (M = 374.88): C: 60.87% H:5.11% N: 7.47% S: 8.55% Cl: 9.46%. Found: C: 60.55% H: 5.20% N: 7.55% S:8.70% Cl: 9.64%.

EXAMPLE 12

1.0 g. of1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineis added portionwise to 3.0 ml. of concentrated sulfuric acid withstirring, and the reaction mixture is left to stand at room temperatureovernight. The mixture is poured onto ice and rendered alkaline. 0.75 g.of1-carboxamido-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 240°C (after recrystallization from 75 % alcohol).

Analysis: Calculated for C₁₄ H₁₅ N₃ O₃ S (M=305.35): C: 55.06 %, H: 4.95%, N: 13.76 %, S: 10.50 %. Found: C: 54.88 %, H: 5.05 %, N: 13.77 %, S:10.17 %.

1.0 g. of the above product is dissolved in the hot mixture of 9 ml. ofwater and 1 ml. of concentrated hydrochloric acid, and the solution isfiltered when hot. Upon cooling, 0.8 g. of crystalline1-carboxamido-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo-[4,3-a]isoquinolinehydrochloride hemihydrate separates from the filtrate; m.p.: 270°-272°C(under decomposition).

Analysis: Found: C: 47.52 %, H: 4.84 %, N: 11.77 %, S: 9.48 %, Cl: 9.89% Calc.: C: 47.93 %, H: 4.88 %, N: 11.98 %, S: 9.14 %, Cl: 10.11 %Empirical formula: C₁₄ H₁₆ N₃ O₃ SCl.1/2 H o (M = 350.82).

EXAMPLE 13

10 ml. of 10 % sodium hydroxide solution and 20 ml. of alcohol are addedto 1.0 g. of1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline,and the mixture is refluxed for 6 hours. The alcohol is distilled off,and the residue is neutralized to a pH 7 of from to 8 with hydrochloricacid. 0.8 g. of1-carboxy-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinemonohydrate are obtained; m.p.: 177°-179°C (after recrystallization from50% alcohol).

Analysis: Calculated for C₁₄ H₁₆ N₂ O₅ S (M = 324.35): C: 51.84 %, H:4.97 %, N: 8.64 %, S: 9.88 %. Found: C: 51.64 %, H: 4.83 %, N: 8.56 %,S: 10.02 %.

EXAMPLE 14

A mixture of 2.87 g. (0.01 moles) of1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazilo[4,3-a]isoquinoline, 1.7 g. (about 0.01 moles) of p-chloro-anilinehydrochloride and 30 ml. of dimethylformamide is refluxed for 10 hours.The precipitate separated on cooling is filtered off. 2.1 g. (53 %) of1-cyano-3-(N-p-chlorophenyl)-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 254°C (after recrystallization fromdichloromethane).

Analysis: Calculated for C₂₀ H₁₆ N₃ O₂ SCl (M = 397.88): N: 10.56 %, Cl:8.91 %. Found: N: 10.40 %, Cl: 9.26 %.

EXAMPLE 15

5 ml. of pyridine and 0.5 ml. of acetic anhydride are added to 0.5 g. of1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline,and the reaction mixture is refluxed for 0.5 hours. The mixture iscooled and diluted with water. 0.6 g. of1-cyano-3-acetimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 223°-225°C (after recrystallization from butanol).

Analysis: Calculated for C₁₆ H₁₅ N₃ O₃ S (M = 329.37): C: 58.34 %, H:4.59 %, N: 12.76 %, S: 9.74 %. Found: C: 58.50 %, H: 4.50 %, N: 13.02 %,S: 10.08 %.

EXAMPLE 16

5 ml. of pyridine and 0.3 ml. of benzoyl chloride are added to 0.5 g. of1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline,and the mixture is refluxed for 0.5 hours. After cooling, the mixture isdiluted with water. 0.6 g. of1-cyano-3-benzoylimino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline is obtained in crystalline state; m.p.: 274°-276°C (afterrecrystallization from a mixture of dimethylformamide and butanol).

Analysis: Calculated for C₂₁ H₁₇ N₃ O₃ S (M = 391.43): C: 64.43 %, H:4.37 %, N: 10.74 %, S: 8.19 %. Found: C: 64.73 %, H: 4.37 %, N: 10.93 %,S: 8.48 %.

EXAMPLE 17

A mixture of 2.87 g. (0.01 moles) of1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinoline,1.2 g. of aminoethanol hydrochloride and 30 ml. of dimethylformamide isrefluxed for 10 hours. The solution is evaporated, and the residue iscrystallized from nitromethane.1-Cyano-3-(N-2-hydroxyethyl)-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo[4,3-a]isoquinoline,melting at 202°-204°C, is obtained.

Analysis: Calculated for C₁₆ H₁₇ N₃ O₃ S (M = 331.39): C: 57.99 %, H:5.17 %, N: 12.68 %. Found: C: 57.79 %, H: 4.93 %, N: 12.72 %.

Example 18

0.5 g. of potassium rhodanide are dissolved in 35 ml. of hot dryalcohol, and 1.0 g. (0.003 moles) of1-(α-bromo)-nitromethylene-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinolineis added to the boiling solution within 20 minutes. The mixture isrefluxed for 3 hours, thereafter left to stand overnight. 0.75 g. of1-nitro-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 220°-221°C (after recrystallization from dryalcohol).

Analysis: Calculated for C₁₃ H₁₃ N₃ O₄ S (M = 307.33): C: 50.81 %, H:4.26 %, N: 13.67 %, S: 10.43 %. Found: C: 51.05 %, H: 4.17 %, N: 13.53%, S: 10.25 %.

EXAMPLE 19

0.66 g. (0.002 moles) of1-cyano-3-imino-8,9-dihydroxy-1,2,3,4-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinehydrochloride dihydrate are dissolved in 20 ml. of hot 50% alcohol, and3.0 ml. of 10% sodium hydroxide solution are added to the mixture. 1 to2 minutes thereafter 1.0 ml. of methyl iodide are added, and the mixtureis refluxed for 3 hours. The crystalline precipitate separated uponcooling is filtered off, washed with 50 % alcohol and dried. 0.4 g. of1-cyano-3-imino-8,9-dimethoxy-1,2,3,4-tetrahydro-1,3-thiazolo[4,3-a]isoquinolineare obtained; m.p.: 229°-230°C.

EXAMPLE 20

20.0 g. of pyridine hydrochloride are added to 6.0 g. of1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride, and themixture is kept for 2 hours in an oil bath of 210°-220°C. The mixture iscooled and a mixture of 6 ml. of concentrated hydrochloric acid and 14ml. of water is added. 5.2 g. of crystalline1-cyano-3-imino-8,9-dihydroxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinolinehydrochloride dihydrate are obtained; m.p.: graduallly decomposes from280°C (after recrystallization from hot water).

Analysis: Calculated for C₁₂ H₁₄ N₃ O₄ SCl (M: 331.78): C: 43.44% H:4.25% N: 12.66% Cl: 10.68% S: 9.66%. Found: C: 43.84% H: 4.37% N: 12.26%Cl: 10.66% S: 10.03 %.

EXAMPLE 21

1.0 g. of1-cyano-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-onis added in portions into 3 ml. of concentrated sulfuric acid withstirring. The reaction mixture is left to stand for 24 hours, thereafterit is poured onto ice. 0.75 g. of1-carboxamido-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-onare obtained; m.p.: 222°-224°C (after recrystallization from 75%alcohol).

Analysis: Calculated for C₁₄ H₁₄ N₃ O₄ S (M = 306.33): C: 54.88 % H:4.61 %, N: 9.14 %, S: 10.47 %. Found: C: 54.65 %, H: 4.41 %, N: 9.38 %,S: 10.50 %.

EXAMPLE 22

120 ml. of 96% alcohol and 27.0 ml. of 10% sodiumhydroxide solution areadded to 12.0 g. ofS-(α-cyano-α-6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-methyl-isothiuroniumbromide, and the mixture is refluxed for 2 hours. Thereafter 6.5 g. ofethyl chloroformate are added dropwise to the boiling mixture within 10minutes, and the mixture is refluxed for further 0.5 hours. Uponcooling, 6.65 g. of1-cyano-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-on separates in crystalline state; m.p.: 205°-207°C(after recrystallization from butanol).

EXAMPLE 23

To 4.0 g. ofS-(α-cyano-α-6,7-dimethoxy-3,4-dihydro-1-isoquinolylmethyl-isothiuronium-bromide50 ml of 96% alcohol and 11.0 ml of 10 % sodium hydroxide solution areadded and the reaction mixture is refluxed. After 2 hours the refluxingsolution is saturated with phosgene and refluxed for a further period of30 minutes. On cooling 2.5 g of1-cyano-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline-3-onecrystallizes, the properties thereof being identical with the productobtained by example 6.

EXAMPLE 24

To a solution of 1.32 g (0.005 moles) ofα-(6,7-dimethoxy-3,4-dihydro-1-isoquinolyl)-thioacetamide and 25 ml ofpyridine, 0.8 g (0.01 mole) of bromide in 5 ml. of methanol are addedunder stirring at 28°-30°C. The reaction mixture is stirred at thistemperature for a further hour and evaporated in vacuo. The residue iscrystallized from anhydrous ethanol. Thus 0.8 g. of2-imino-2H,4H-5,6-dihydro-8,9-dimethyoxy-1,2-thiazolo[3,2-a]isoquinoline-hydrobromideare obtained. Mp.: 194°- 195°C (decomposition).

Analysis for the formula C₁₃ H₁₄ N₂ O₂ BrS: Calc. : C: 45.62%, H: 4.12%,N: 8.18%, Br: 23.34%, S: 9.36%. Found: C: 45.35%, H: 4.2%, N: 8.1%, Br:23.45%, S: 9.45%.

What we claim is: 1.1-cyano-3-imino-3,4,5,6-tetrahydro-8,9-dimethoxy-1,3-thiazolo [4,3-a]isoquinoline.